Liquid protein formulations containing water soluble organic dyes

Abstract

Concentrated, low-viscosity, low-volume liquid pharmaceutical formulations of proteins have been developed. Such formulations can be rapidly and conveniently administered by subcutaneous or intramuscular injection, rather than by lengthy intravenous infusion. These formulations include low-molecular-weight and/or high-molecular-weight proteins, such as mAbs, and viscosity-lowering water soluble organic dyes.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 030,521, filed Jul. 29, 2014, entitled “Low-Viscosity Protein Formulations Containing Hydrophobic Salts;” U.S. Provisional Application No. 62 / 026,497, filed Jul. 18, 2014, entitled “Low-Viscosity Protein Formulations Containing GRAS Viscosity-Reducing Agents;” U.S. Provisional Application No. 62 / 008,050, filed Jun. 5, 2014, entitled “Low-Viscosity Protein Formulations Containing Ionic Liquids;” U.S. Provisional Application No. 61 / 988,005, filed May 2, 2014, entitled “Low-Viscosity Protein Formulations Containing Organophosphates;” U.S. Provisional Application No. 61 / 946,436, filed Feb. 28, 2014, entitled “Concentrated, Low-Viscosity Infliximab Formulations;” U.S. Provisional Application No. 61 / 943,197, filed Feb. 21, 2014, entitled “Concentrated, Low-Viscosity, High-Molecular-Weight Protein Formulations;” U.S. Provisional Application No. 61 / 940,227,...

AI Technical Summary

Benefits of technology

[0025]In some embodiments, the protein and viscosity-lowering water soluble dye are provided in a lyophilized dosage unit, sized for reconstitution with a sterile aqueous pharmaceutically acceptable vehicle, to yield the concentrated low-viscosity liquid formulations. The presence of the viscosity-lowering water soluble dye(s) facilitates and/or accelerates the reconstitution of the lyophilized dosage unit compared to a lyophilized dosage unit not containing a viscosity-lowering wat...

Problems solved by technology

These high concentrations often result in very viscous formulations that are difficult to administer by injection, cause pain at the site of injection, are often imprecise, and/or may have decreased chemical and/or physical stability.

These characteristics result in manufacturing, storage, and usage requirements that can be challenging to achieve, in particular for formulations having high concentrations of high-molecular-weight proteins, such as mAbs.

High protein concentrations pose challenges relating to the physical and chemical stability of the protein, as well as difficulty with manufacture, storage, and delivery of the protein formulation.

One problem is the tendency of proteins to aggregate and form particulates during processing and/or storage, which makes manipulations during further processing and/or delivery difficult.

Concentration-dependent degradation and/or aggregation are major challenges in developing protein formulations at higher concentrations.

In addition to the potential for non-native protein aggregation and particulate formation, reversible self-association in aqueous solutions may occur, which contributes to, among other things, increased viscosity that complicates delivery by injection.

Increased viscosity is one of the key challenges encountered in concentrated protein compositions affecting both production processes and the ability to readily deliver such compositions by conventional means.

Highly viscous liquid formulations are difficult to manufacture, draw into a syringe, and inject subcutaneously or intramuscularly.

The use of force in manipulating the viscous formulations can lead to excessive frothing, which may further denature and inactivate the therapeutically active protein.

High viscosity solutions also require larger diameter needl...

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